Synthesis and pharmacological evaluation of [(4-arylpiperazin-1-yl)-alkyl]-carbamic acid ethyl ester derivatives as potential anxiolytic agents

Abstract

On the basis of our earlier studies, a series of N-{4-[4-(aryl) piperazin-1-yl]-phenyl}-amine derivatives containing terminal carbamoyl fragment with alkyl spacer of different lengths (15-20) were synthesized as ligands, for 5-hydroxytryptamine-1A (5-HT(1A)) receptor. Molecular modeling studies were undertaken to explain the influence of spacer length on ligands affinity towards 5-HT(1A) receptor. Compound 19 showed all the specific interactions responsible for recognition. The protonated amine of the ligand forms an ionic hydrogen bond with the negatively charged Asp116 of transmembrane3 helix (TM3), while the carbamoyl moiety interacts with Asn386 and Tyr390 of TM7. The aryl group is involved in forming a CH-π interaction with Phe362. The strong interaction of compound 19 with 5-HT(1A) receptor in docking studies was confirmed by radio ligand binding studies. Compound 19 showed high affinity for the receptor (Ki = 0.018 nM). In vivo pharmacological testing of compound 19 (3 mg/kg body weight) showed increased open arm entries, as well as time spent in Elevated plus Maze test. Toxicological analysis also revealed no significant biochemical or morphological alterations in the vital organs of experimental animals. Furthermore our results suggest that these compounds share some pharmacological effects with established anxiolytics and might prove to be effective compounds for the treatment of anxiety.